SAN DIEGO — Results of two phase III studies of pirfenidone, an oral antifibrotic and anti-inflammatory agent, have shown that the drug could slow the deterioration of lung capacity in patients with idiopathic pulmonary fibrosis.
The 72-week-long trials, known as CAPACITY 1 and CAPACITY 2, enrolled 779 patients at 110 sites in 11 countries.
“The findings of the CAPACITY trials, coupled with the results of the phase II and phase III studies in Japan and the urgent unmet medical need, suggest that pirfenidone may provide a meaningful clinical benefit in patients with IPF,” trial cochair Paul Noble said during an international conference of the American Thoracic Society.
Manufactured by InterMune Inc., pirfenidone is currently approved in Japan for the treatment of IPF. InterMune expects to submit a New Drug Application for the agent to the Food and Drug Administration in the summer of 2009.
Patients were eligible for the studies if they had a diagnosis of pulmonary fibrosis confirmed by CT scan or by biopsy and if they had a forced vital capacity (FVC) that was 50% of predicted value or greater and a diffusing capacity of the lung for carbon monoxide that was 35% of predicted value or greater.
The 344 patients in CAPACITY 1 were randomized to receive pirfenidone 2,403 mg/day or placebo for 72 weeks, while the 435 patients in CAPACITY 2 were randomized to receive either pirfenidone 2,403 mg/day, pirfenidone 1,197 mg/day, or placebo for 72 weeks. The primary end point was change in percent predicted FVC from baseline to week 72.
The mean age of patients in CAPACITY 1 was 68 years, while the mean age of CAPACITY 2 patients was 67 years, said Dr. Noble, professor of medicine and chief of pulmonary, allergy, and critical care medicine at Duke University, Durham, N.C.
In CAPACITY 2, patients in the treatment group achieved a significant reduction in change in percent predicted FVC at week 72, compared with placebo (−6.49% vs. −9.55%, respectively), and an increase in progression-free survival time (hazard ratio of 0.64). The treatment group also demonstrated a favorable effect on change in FVC category (P = .001).
In CAPACITY 1, there was no significant mean change in percent predicted FVC at week 72 between the treatment and placebo groups (−6.49% vs. −7.23%, respectively), but there was evidence of a treatment benefit at each assessment through week 48. “CAPACITY 1 did not achieve statistical significance on the primary end point,” Dr. Noble said. “However, results were generally consistent with and supportive of CAPACITY 2.”
According to a prepared statement from InterMune, a pooled analysis of categorical FVC change from the two studies “showed that 30% fewer patients experienced a 10% or greater decrease in FVC at week 72 in the pirfenidone group than in the placebo group. This magnitude of decline is considered clinically meaningful, as a 10% decline in percent predicted FVC has been shown in multiple studies to be an independent predictor of mortality in patients with IPF. In addition, 40% more patients in the pirfenidone group did not experience a decline in percent predicted FVC at week 72 versus baseline compared to those who received placebo.”
At the meeting, Dr. Noble reported that the pattern of adverse events in both trials was generally comparable to those observed in previous clinical studies of pirfenidone. The most common adverse events in the pirfenidone group compared with placebo were nausea (35% vs. 18% in CAPACITY 2, and 38% vs. 16% in CAPACITY 1), rash (31% vs. 10%, and 34% vs. 13%), fatigue (28% vs. 21%, and 33% vs. 20%), diarrhea (25% vs. 17%, and 33% vs. 21%), dyspepsia (17% vs. 9%, and 21% vs. 6%), and dizziness (19% vs. 10%, and 18% vs. 10%).
Rash was generally mild to moderate in both studies; only two patients (one in each CAPACITY study) who received pirfenidone had a severe rash.
Researchers also analyzed the incidence of patients who died during the treatment period, which was defined as the time between receiving the first dose of treatment and 28 days after receiving the last dose. In CAPACITY 1, 5% of the pirfenidone group died during the treatment period, compared with 9% of the placebo group. In CAPACITY 2, 6% of pirfenidone patients died during the treatment period, compared with 8% of placebo patients.
“CAPACITY 2 demonstrated a statistically significant and a clinically meaningful effect on the primary end point of change in percent predicted FVC and the secondary end points of progression-free survival and categorical change in percent predicted FVC,” Dr. Noble concluded. “CAPACITY 1 did not, and it failed to achieve statistical significance on the primary end point.”